Project Summary Hemangiomas are the most common tumors in infants. These tumors can threaten the child's life (1%), threaten the development of vital structures (10%) and cause residual deformity in 50% of affected children. The majority occur in the head and neck area resulting in obvious physical deformity that causes tremendous distress for parents. Despite these significant complications, the majority of affected children do not receive treatment because of the high risks associated with current pharmacologic therapies. The absence of safe therapeutic alternatives is a critical barrier to care and good clinical outcomes for children with hemangiomas. In the previous cycle of funding we discovered markedly elevated levels of microRNA (miR)126 in the urine of children with proliferating hemangiomas indicating its potential usefulness as a biomarker. It is also markedly upregulated (104 x) in our validated murine model using EOMA cells and transdermal delivery of miR 126 inhibitor resulted in complete tumor regression in the murine model. miR126 is the predominant miR transcript expressed by endothelial cells during development and the transcription factor GATA binding protein 2 (GATA2) is critical driver of fetal endothelial cell development. Both are upregulated in EOMA cells, which supports the conceptual paradigm that endothelial cells in hemangiomas retain a persistent fetal phenotype, i.e. they are fetal rests. This proposal will establish miR126 as a critical driver of hemangioma development and proliferation and GATA2 as a key transcriptional regulator of miR126 biogenesis. We have previously reported that a standardized natural berry extract (NBE) can effectively limit hemangioma development and proliferation using the EOMA model. This safe nutritional intervention also inhibits the GATA2/miR126 axis in EOMA cells. This proposal will test the ability of NBE to inhibit hemangioma proliferation in the murine model and in children with hemangiomas. Changes in urinary levels of miR126 in response to NBE therapy will be measured to establish utility as a biomarker. The innovation in this proposal includes: the use of important contextual cues from fetal development to inform lines of investigation, establishing the critical significance of miR regulation of hemangioma proliferation, the identification of a safe nutritional intervention with pharmacokinetic data to determine first in human dosing, and the identification and testing of a biomarker for hemangioma. Successful completion of this proposal will change clinical management of hemangioma by making treatment safely available to all affected children in an effort to prevent death, disability or deformity caused by these tumors.